Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

Rapakko, Katrin; Allinen, Minna; Syrjäkoski, Kirsi; Vahteristo, Pia; Huusko, Pia; Vähäkangas, Kirsi; Eerola, Hannaleena; Kainu, Tommi; Kallioniemi, Olli; Nevanlinna, Heli; Winqvist, Robert

doi:10.1054/bjoc.2000.1530

Cited by 40 publications

(25 citation statements)

References 29 publications

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“…Consistent with our work, a few studies have reported several potential pathogenic mutations of p53 in individuals with evidence of hereditary susceptibility to breast cancer outside LFS and LFL families in different ethnic groups [3,[13][14][15][16][17][18][19], but almost all the identified variants showed to be single point missense mutations in contrast to a novel protein-truncated mutation identified in our population. Particularly, as the testing method used in our study, DHPLC has been confirmed to be a robust and sensitive screening technique [20].…”

Section: Discussionsupporting

confidence: 91%

Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population

Cao

Jin

Shi

et al. 2009

Breast Cancer Res Treat

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Germ line mutations in the tumor suppressor gene, p53, are known to cause Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL). We sought to identify p53 germ line mutations in potential hereditary breast cancer patients without LFS/LFL phenotype, which will help us establish the genetic testing strategy for p53 in Chinese high-risk breast cancer families. We screened all coding exons and intron-exon boundaries of p53 in 240 women with early-onset breast cancer or affected relatives from four breast disease clinical centers in China by utilizing PCR-DHPLC and DNA sequencing analysis. Additionally, three cell lines (H1299, MCF-7, and MDA-MB-231) were transfected with pEGFP-N1-only or pEGFP-N1 vectors expressing either wild-type or two novel identified mutant p53. And then we performed flow cytometry analysis in the transfected cells to determine the status of cell apoptosis, and real-time PCR as well as western blot analysis to ascertain the expression of p53, p21, and p27. Two novel germ line mutations (563T > C and 643_660del18) were detected in two independent families. Neither of them, however, was present in the 768 normal controls. Functional assays revealed that the ability to trigger cell apoptosis and transcriptional activation of target gene under similar expression of p53 were lower in two mutants versus wild-type p53. Deleterious mutations of p53 seemed to be responsible for approximately 1% of non-BRCA1/BRCA2 hereditary breast cancer in Chinese population, and our findings suggested that p53 should be included in genetic testing of Chinese non-LFS/non-LFL high-risk breast cancer families.

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Section: Discussionsupporting

confidence: 91%

Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population

Cao

Jin

Shi

et al. 2009

Breast Cancer Res Treat

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“…The frequency of mutation-positive families identified in our study is consistent with independent reports suggesting that germline TP53 mutations are rare in multiple case breast cancer families, possibly accounting for <1% of such families [25][26][27][28][29][30][31][32][34][35][36][37]. The higher frequency of mutation-positive families in our study is likely due to the selection criteria, which excluded BRCA1 and BRCA2 mutation-positive families.…”

Section: Discussionsupporting

confidence: 89%

“…The frequency of TP53 germline mutations has been investigated in multiple studies [25][26][27][28][29][30][31][32], suggesting that they account for <1% of breast cancer families. However, the contribution of TP53 to breast cancer in the French Canadian population is not known.…”

Section: Introductionmentioning

confidence: 99%

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

Arcand

Maugard

Ghadirian

et al. 2007

Breast Cancer Res Treat

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About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this gene because of a family history consistent with Li-Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutation-negative cancer families, and a mutation-positive family was identified. However, pedigree inspection and expansion of mutation-positive families with the same mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li-Fraumeni-like (LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian cancer families of French Canadian descent.

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“…Interestingly, these mutations have also been reported in breast carcinomas. [36][37][38] EGFR/erbB-1 belongs to a receptor family with tyrosine kinase activity whose gene is located on chromosome 7p12. The EGFR signaling that mediates proliferation, migration, invasion, and suppression of apoptosis, can be blocked by a growing number of drug inhibitors.…”

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confidence: 99%

A potential role for targeted therapy in a subset of metastasizing adnexal carcinomas

et al. 2011

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Metastasizing adnexal carcinomas are rare; thus, currently there is no uniform treatment guideline. Chemotherapeutic drugs that selectively target cancer-promoting pathways may complement conventional therapeutic approaches. We performed immunohistochemistry (epidermal growth factor receptor (EGFR), HER2, and CD117), EGFR and ERBB2 fluorescence in situ hybridization (FISH), and multiplexed SNaPshots genotyping (testing for recurrent mutations in 15 cancer genes including BRAF, EGFR, KRAS, PIK3CA, and TP53) on primary tumors and corresponding metastases of 14 metastasizing adnexal carcinomas (three apocrine, six eccrine, two hidradenocarcinomas, two porocarcinomas, and one aggressive digital papillary adenocarcinoma). Metastasis to regional lymph node was most common, followed by skin and then lungs. Follow-up was available in 12 patients (5 months to 8 years) with 1 died of widespread metastases. Although EGFR overexpression was a prevalent feature in this cohort, seen in 7/11 (64%) primary tumors and 10/14 (71%) metastases; FISH for EGFR gene amplification was negative in 9 tested primary tumors and 12 metastases. FISH of the one primary tumor and three metastases with 2 þ HER2 overexpression revealed a low level of ERBB2 gene amplification in one apocrine carcinoma and corresponding metastasis. CD117 expression was seen only in rare cases. PIK3CA (2/12, 17%) and TP53 (3/12, 25%) mutations were detected in two (one hidradenocarcinoma, one porocarcinoma) and three (one eccrine, one hidradenocarcinoma, and one aggressive digital papillary adenocarcinoma) cases, respectively. The role of EGFR inhibitor therapy in metastasizing adnexal carcinomas with protein overexpression remains unclear. Targeted therapy including PI3K pathway inhibitors might be a potential treatment for rare cases of adnexal carcinomas with metastases.

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Germline TP53 alterations in Finnish breast cancer families are rare and occur at conserved mutation-prone sites

Cited by 40 publications

References 29 publications

Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population

Identification and characterization of two novel germ line p53 mutations in the non-LFS/non-LFL breast cancer families in Chinese population

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

A potential role for targeted therapy in a subset of metastasizing adnexal carcinomas

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